Asymmetric Synthesis of 2′-C-Methyl-4′-selenonucleosides as Anti-Hepatitis C Virus (HCV) Agents

In search of a new template for anti-hepatitis C virus (HCV) agents, we designed and synthesized the 2′-C-methyl-4′-selenopyrimidine and -purine nucleosides and their phosphoramidate prodrugs to replace a furanose oxygen of anti-HCV nucleos(t)ides with a selenium atom on the basis that selenium is a chemical isostere of oxygen. These nucleosides are expected to show different physicochemical properties such as better lipophilicity which might enhance the penetration across cell membranes and the conformational constraint induced by a bulky selenium atom in the sugar ring. The 2′-C-methyl-4′-selenopyrimidine and -purine nucleosides 8 and 9 were synthesized from 2-C-methyl-d-ribono-γ-lactone (14) via construction of 2-C-methyl-d-selenosugar 18 through C-4 epimerization and SN2 cyclization with Se2– as key steps. The key 4′-selenosugar was converted to the 2′-C-methyl-4′-selenopyrimidine and -purine nucleosides using Pummerer-type rearrangement and Vorbruggen glycosylation, respectively. In addition, the Pro...